BACKGROUND: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. METHODS: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. RESULTS: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1x10(-5) and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1x10(-5) and 4.1x10(-10)). CONCLUSIONS: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.
BACKGROUND:Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. METHODS: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. RESULTS: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1x10(-5) and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1x10(-5) and 4.1x10(-10)). CONCLUSIONS: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.
Authors: Linda J W Bosch; Yanxin Luo; Victoria V Lao; Petur Snaebjornsson; Geert Trooskens; Ilse Vlassenbroeck; Sandra Mongera; Weiliang Tang; Piri Welcsh; James G Herman; Miriam Koopman; Iris D Nagtegaal; Cornelis J A Punt; Wim van Criekinge; Gerrit A Meijer; Raymond J Monnat; Beatriz Carvalho; William M Grady Journal: Clin Cancer Res Date: 2016-04-27 Impact factor: 12.531
Authors: Terje Ahlquist; Irene Bottillo; Stine A Danielsen; Gunn I Meling; Torleiv O Rognum; Guro E Lind; Bruno Dallapiccola; Ragnhild A Lothe Journal: Neoplasia Date: 2008-07 Impact factor: 5.715
Authors: David A Ahlquist; Daniel J Sargent; Charles L Loprinzi; Theodore R Levin; Douglas K Rex; Dennis J Ahnen; Kandice Knigge; M Peter Lance; Lawrence J Burgart; Stanley R Hamilton; James E Allison; Michael J Lawson; Mary E Devens; Jonathan J Harrington; Shauna L Hillman Journal: Ann Intern Med Date: 2008-10-07 Impact factor: 25.391
Authors: Efterpi Kostareli; Dana Holzinger; Olga Bogatyrova; Thomas Hielscher; Gunnar Wichmann; Michaela Keck; Bernd Lahrmann; Niels Grabe; Christa Flechtenmacher; Christopher R Schmidt; Tanguy Seiwert; Gerhard Dyckhoff; Andreas Dietz; Daniela Höfler; Michael Pawlita; Axel Benner; Franz X Bosch; Peter Plinkert; Christoph Plass; Dieter Weichenhan; Jochen Hess Journal: J Clin Invest Date: 2013-05-01 Impact factor: 14.808